β-lactam antibiotics are commonly prescribed antibiotics that are active against both gram-positive and gram-negative organisms. See Goodman and Gilman's, The Pharmacological Basis of Therapeutics, Ninth Ed., 1996 (Goodman and Gilman's). Penicillins include penicillins G and V which are active against gram-positive cocci, naficillin which is active against penicillinase-producing Staphylococcus aureus and ampicillin which has an improved gram-negative spectrum of activity. Unfortunately, bacterial resistance to β-lactam antibiotics is growing. A major mechanism of resistance involves the production of β-lactamases by the bacteria. β-lactamases cleave the β-lactam ring generating penicilloic acid, which is not bacteriocidal.
β-lactamases can be inhibited by molecules which bind to the β-lactamases, acting as competitive substrates for the enzymes. One such molecule, clavulanic acid, binds irreversibly to the β-lactamases, irreversibly inhibiting the enzyme. Clinically, the addition of β-lactamase inhibitors to penicillins is very important because it extends the spectrum of bacteriocidal activity. For example, the combination of amoxicillin and clavulanic acid is effective against the β-lactamase-producing strains of staphylococci, H. influenza, gonococci and E. coli. The addition of clavulanic acid to ticarcillin extends its bacteriocidal activity to include aerobic gram-negative bacilli, Staphylococcus aureus as well as Bacteroides species. Other β-lactamases inhibitors include, sulbactam and tazobactam.
Unfortunately, β-lactamase inhibitors such as clavulanic acid are unstable in aqueous media. U.S. Pat. No. 6,177,421. Clavulanic acid is susceptible to hydrolytic degradation. There exists a narrow range of pH and temperature where the molecule is most stable. Wildfeuer et al. Arzneimittelforschung 41(1):70-73 (1991).
Given the growth of antibiotic resistant bacteria and the importance of penicillins as a first-line therapy, there exists a continuing need to develop formulations containing β-lactamase inhibitors that are stable.